The present invention relates to a novel piperidine compound, a salt thereof or a hydrate of them, a production process thereof, and a pharmaceutical composition comprising these compounds and the like and a preparation thereof.
The atrial fibrillation, which is one type of arrhythmia, is a condition in which the atrium does not carry out regular excitation and contraction in accordance with stimulation from the sinoatrial node, and frequently repeats the excitation at random, and is classified in paroxysmal atrial fibrillation and chronic atrial fibrillation. In many cases, crisis occurs as the complication of organic heart diseases, such as mitral valve disease, coronary artery disease, hypertensive heart disease, thyrotoxicosis (which are four major basic diseases), increases, and lone atrial fibrillation only causing atrial fibrillation is also reported. Further, a condition in heart failure is often exhibited in addition to palpitation and chest discomfort, and thrombus is formed in the left atrium, which can provoke thromboembolism in various organs of system. Although the treatment of atrial fibrillation (the termination of paroxysm, the prevention of recurrence, and the like) differs in the cases of paroxysmal atrial fibrillation and chronic atrial fibrillation, the effectiveness of non-medication is insufficient in both cases, and the administration of an antiarrhythmic drug is designated as the first choice at present. There are known antiarrhythmics, such as Class I drugs of Vaughan Williams classification (Class I: a drug suppressing the conduction in atrial muscle by selective blocking of Na+ channel and inhibiting the reentry circuit), Class II drugs (Class II: xcex2-adrenergic receptor blocker), Class III drugs (Class III: a drug of selectively blocking K+ channel and prolonging the action potential duration), Class IV drugs (Class IV: Ca+ channel blocker), and the like. However, a drug of inhibiting the reentry circuit of potential in atrial muscle is effective for termination of atrial fibrillation, and it is considered that the class I antiarrhythmic drug and the class III antiarrhythmic drug are effective. Concerning this kind of antiarrhythmics, many reports have been hitherto disclosed, and, for example, the inventions relating to piperidine compounds as antiarrhythmics are disclosed in Japanese patent Application No. 62-281858, JP-A 6-501242, JP-A 7-502273, JP-A 8-511014 etc., in addition to the inventions relating to the antiarrhythmics disclosed in JP-A 9-505597, JP-A 8-511014, WO96/13479, etc.
However, since the class I antiarrhythmic drug has a negative inotropic effect (the reduction of the pumping function of heart) based on the Na+ channel inhibitory action, it has been a problem in that it causes the deterioration or exasperation of heart failure. To the contrary, the class III antiarrhythmic drug does not exhibit such an effect and is superior in only extending the refractory period, but a conventional class III antiarrhythmic drug is not always effective in the termination rate of atrial fibrillation, extends also the refractory period of atrial muscle, and often extends the refractory period of atrial muscle at a normal time than at tachycardia (reverse use-dependency), and therefore it has been a problem to induce ventricular arrhythmia at a dose of showing a medicinal effect.
On the other hand, it is also known that the compound having the Na+ channel inhibitory action is useful for remedy of various neuralgia (for example, postherpetic neuralgia, diabetic neuralgia, HIV neuralgia etc.). For example, Lidoderm in remedy for postherpetic neuralgia, Carbamazepine in trigeminal neuralgia, Na+ channel inhibitor as antiarrhythmic (for example, Mexiletin), Na+ channel inhibitors as antidepressant and anticonvulsant (for example, Amitriptyline, Carbamazepine) and the like are used as various antineuralgic remedies. In addition to these, there are several reports (Pain. 83 (1999) 389-400: European Journal of Pain 2 (1998) 3-14; Pain. 73 (1997) 123-139) concerning the fact that arrhythmia drug (Mexiletine, Lidocaine) is effective as analgesic.
However, since a conventional N+ channel inhibitor has an equal effect to the heart and nerves in the remedy of a conventional neuralgia, the dose of a Na+ channel inhibiting compound cannot be increased, and a distinct analgesic effect could not be exhibited.
A drug which exhibits a superior Na+ channel inhibitory action, that satisfies the requirements of pharmacological activity, a dose, safety and the like, as pharmaceuticals, and effective in clinical use, has been not found. Namely, it is the object of the present invention to investigate and find a superior Na+ channel inhibiting compound which solves the above-mentioned problems.
The present inventors have intensively studied in view of the above-mentioned circumstances, and as a result, have succeeded in synthesizing a compound which is a quite novel piperidine compound represented by the formula (I): 
(wherein the ring A indicates a ring represented by the formula: 
(wherein R1 means (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) an optionally substituted C1-6 alkyl group, (5) an optionally substituted C2-6 alkenyl group, (6) an optionally substituted C2-6 alkynyl group, (7) an optionally substituted C3-8 cycloalkyl group, (8) an optionally substituted C3-8 cycloalkenyl group, (9) an optionally substituted C1-6 alkoxy group, (10) an optionally substituted C1-6 alkylthio group, (11) an optionally substituted C1-6 alkylsulfinyl group, (12) an optionally substituted C1-6 alkylsulfonyl group, (13) an optionally substituted C6-14 aromatic hydrocarbon cyclic group or (14) an optionally substituted 5- to 14-membered aromatic heterocyclic group;
R2 means (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C2-6 alkenyl group, (4) an optionally substituted C2-6 alkynyl group, (5) an optionally substituted C3-8 cycloalkyl group, (6) an optionally substituted C3-8 cycloalkenyl group, (7) an optionally substituted amino group, (8) an optionally substituted C6-14 aromatic hydrocarbon cyclic group or (9) an optionally substituted 5- to 14-membered aromatic heterocyclic group; and
R3 means (1) an optionally substituted C1-6 alkoxy group, (2) an optionally substituted C2-6 alkenyloxy group, (3) an optionally substituted C3-7 cycloalkyloxy group or (4) an optionally substituted C3-7 cycloalkenyloxy group);
W means (1) a single bond, (2) an optionally substituted C1-6 alkylene group, (3) an optionally substituted C2-6 alkenylene group, (4) an optionally substituted C2-6 alkynylene group or (5) a group represented by the formula xe2x80x94Uxe2x80x94Vxe2x80x94 (wherein U means (i) a single bond, (ii) an oxygen atom, (iii) a sulfur atom, (iv) a group represented by the formula xe2x80x94NHxe2x80x94, (v) an optionally substituted C1-6 alkylene group, (vi) an optionally substituted C2-6 alkenylene group or (vii) an optionally substituted C2-6 alkynylene group; V means (i) a single bond, (ii) an optionally substituted C1-6 alkylene group, (iii) an optionally substituted C2-6 alkenylene group, (iv) an optionally substituted C2-6 alkynylene group, (v) an oxygen atom, (vi) a sulfur atom, or (vii) a group represented by the formula xe2x80x94COxe2x80x94, (viii) xe2x80x94SOxe2x80x94 or (ix) xe2x80x94SO2xe2x80x94, provided that the case where U and V mean the same group in the above definition is excluded, and one of U and V means a single bond, an optionally substituted C1-6 alkylene group, an optionally substituted C2-6 alkenylene group or an optionally substituted C2-6 alkynylene group);
Z means (1) an optionally substituted C6-14 aromatic hydrocarbon cyclic group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group or (3) a group represented by the formula xe2x80x94N(R4)R5 (wherein R4 and R5 may be the same as or different from each other and each represents (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C2-6 alkenyl group, (iv) an optionally substituted C2-6 alkynyl group, (v) an optionally substituted C3-8 cycloalkyl group, (vi) an optionally substituted C3-8 cycloalkenyl group, (vii) an optionally substituted C6-14 aromatic hydrocarbon cyclic group, (viii) an optionally substituted 5- to 14-membered aromatic heterocyclic group or (ix) a C1-6 aliphatic acyl group, or (x) R4 and R5 may be bound together to form a 3-to 8-membered nitrogen-containing cyclic group); and
l represents an integer of (0 to 6), and further, have found that these compounds, etc. have a superior N+ channel inhibitory action, and are useful for treating or preventing a disease against which the Na+ channel inhibitory action is useful for the treatment and prevention (for example, arrhythmia (in addition to this, the removal of a patient""s stress caused by an attack of atrial fibrillation, for example, palpitation, chest discomfort, heart failure, thrombus in left atrium, thromboembolism, seizure), various neuralgia (for example, diabetic neuralgia, HIV neuralgia, postherpetic neuralgia etc.) etc.). Thus, they have completed the present invention.
Namely, the present invention is 1) a compound represented by the above-mentioned formula (I), a salt thereof or a hydrate of them; 2) in the above-mentioned 1), W may be a group represented by the formula xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94(CH2)2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH(CN)xe2x80x94, xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94NHxe2x80x94SO2xe2x80x94 or xe2x80x94CH2xe2x80x94NHxe2x80x94SO2xe2x80x94, 3) in the above-mentioned 1), w may be a group represented by the formula xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x80x94CHxe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94, 4) in the above-mentioned 1), Z may be an optionally substituted C6-14 aromatic hydrocarboncyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group, 5) in the above-mentioned 1), Z may be an optionally substituted phenyl group, pyridyl group or thienyl group, 6) in the above-mentioned 1), Z may be a C6-14 aromatic hydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclic group, and the ring may be respectively substituted with one or more groups selected from (1) a hydroxyl group, (2) a halogen atom, (3) a cyano group, (4) an optionally substituted C1-6 alkyl group, (5) an optionally substituted C3-8 cycloalkyl group, (6) an optionally substituted C1-6 alkoxy group, (7) an optionally substituted C3-8 cycloalkyloxy group, (8) an optionally substituted C1-6 alkylthio group, (9) an optionally substituted C6-14 aryloxy group, (10) an optionally substituted 5- to 14-membered hetero aryloxy group, (11) an optionally substituted amino group, (12) an optionally substituted 5- to 14-membered aromatic heterocyclic group, (13) an optionally substituted 5- to 14-membered non aromatic heterocyclic group, (14) a C1-6 alkylsulfonyl group and (15) a C1-4 alkylenedioxy group, 7) in the above-mentioned 1), Z may be a group represented by the formula xe2x80x94N(R4)R5 (wherein R4 and R5 have the same meanings as defined above, respectively), 8) in the above 7), R4 and R5 may be the same as or different from each other and each represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C6-14 aryl C1-6 alkyl group or an optionally substituted heteroaryl C1-6 alkyl group, 9) in the above-mentioned 7), R4 and R5 may be bound together to form an optionally substituted 3- to 8-membered nitrogen-containing cyclic group, 10) in the above-mentioned 9), Z may be a piperidyl group which may be an optionally substituted piperidyl group, an optionally substituted piperazyl group or an optionally substituted morpholinyl group, 11) in the above-mentioned 1), l may be an integer of 1, 12) in the above-mentioned 1), the ring A may be a ring represented by the formula: 
(wherein R1 and R2 have the same meanings as defined above, respectively), 13) in the above-mentioned 12), R1 may be a hydrogen atom, a halogen atom or a C1-6 alkyl group, 14) in the above-mentioned 12), R1 may be a hydrogen atom, 15) in the above-mentioned 12), R2may be a hydrogen atom or an optionally substituted C1-6 alkyl group, 16) in the above-mentioned 1), the ring A may be a ring represented by the formula: 
wherein R1 and R3 have the same meanings as defined above, respectively, 17) in the above-mentioned 16), R3 may be a hydroxyl group or a C1-6 alkoxy group, 18) in the above-mentioned 1), the bonding position of the group xe2x80x94Wxe2x80x94Z may be 2- or 4-position of a piperidine ring. Further, the present invention is 19) a compound represented by the above-mentioned formula: 
(wherein R1, R2, W, Z and l have the same meanings as defined in the above claim 1), a salt thereof or a hydrate of them, 20) a compound represented by the formula: 
(wherein R1, W and Z have the same meanings as defined in the above claim 1, respectively; and la represents an integer of 1 or 2), a salt thereof or a hydrate of them, 21)
1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethyloxy)phenyl]ethyl]piperidine,
1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine,
1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-(fluorophenyl)ethyl]piperidine,
1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(isobutyloxy)phenyl]ethyl]piperidine,
1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine,
1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine,
1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(benzyloxy)phenyl]-1-ethenyl]piperidine,
1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine,
1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(Z)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine,
1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine,
1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-cyclohexylmethyloxy)phenyl]-1-ethynyl]piperidine,
1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2,4-(difluorophenoxy)methyl]piperidine or
1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2,5-(difluorophenoxy)methyl]piperidine, a salt thereof or a hydrate of them, 22) a process for producing the compound described in the above-mentioned 1), a salt thereof or a hydrate of them, which comprises the step of reacting a compound represented by the formula: 
(wherein the ring A and l have the same meaning as in the fore-mentioned definition according to claim 1, respectively; and L represents a leaving group), a salt thereof or a reactive derivative of them, with a compound represented by the formula: 
(wherein W and Z have the same meanings as defined in the above claim 1, respectively), 23) a pharmaceutical composition comprising a compound represented by the formula: 
(in the formula, the respective symbols have the same meanings as defined in the above claim 1), a salt thereof or a hydrate of them, 24) the composition in the above-mentioned 23) may be a sodium channel inhibitor or a potassium channel inhibitor, 25) the composition in the above-mentioned 23) may be an agent for preventing or treating arrhythmia, 26) the composition in the above-mentioned 23) may be the class III antiarrhythmic drug of Vaughan Williams classification, 27) the composition in the above-mentioned 23) may be an analgesic, 28) the composition in the above-mentioned 23) may be an agent for treating or preventing neuralgia, further, 29) the neuralgia in the above-mentioned 28) may be diabetic neuralgia, HIV neuralgia, postherpetic neuralgia, trigeminal neuralgia, stump pain, postspinal injury pain, thalamic pain or poststroke pain.
The present invention provides use of the compound represented by the above formula (I), a salt thereof or a hydrate of them, for producing a sodium channel inhibitor or a potassium channel inhibitor, an agent for treating or preventing arrhythmia, the class III antiarrhythmic drug of Vaughan Williams classification, an analgesic, and an agent for treating or preventing neuralgia.
Further, the present invention provides a method for preventing or treating a disease against which a sodium channel inhibitiory action or a potassium channel inhibitory action is effective for the prevention or therapy, by administering a pharmacologically effective amount of the compound represented by the above formula (I), a salt thereof or a hydrate of them to a patient.
Further, the present invention provides a method for preventing or treating arrhythmia, the class III antiarrhythmia drug of Vaughan Williams classification, pain and neuralgia, by administering a pharmacologically effective amount of the compound represented by the above formula (I), a salt thereof or a hydrate of them to a patient.
The meanings of the symbols, terms etc. described in the specification of the present application are indicated below, and the present invention is illustrated in detail.
The structural formula of a compound sometimes represents a fixed isomer in the specification of the present application for convenience, but the present invention includes all of geometrical isomers which occur in the structure of the compound, optical isomers based on an asymmetric carbon, stereo-isomers, the isomers of tautomers and the like, and a mixture of the isomers. The present invention is not limited to the description of the formulae for convenience, and may include one of the isomers and a mixture thereof. Accordingly, in the compounds of the present invention, there may exist an optical activator and a racemic body which have an asymmetric carbon atom in the molecule, but they are not limited in the present invention, and both of them are included therein. Further, polymorphism sometimes exists, but is not similarly limited, and any of crystal forms may be single or a mixture of crystal forms, and may be a hydrate in addition to an anhydride. A so-called metabolite which is occurred by decomposing the compounds according to the present invention in vivo is also included within the scope of claim for patent of the present application.
The xe2x80x9carrhythmiaxe2x80x9d in the specification of the present application is a general name of cases in which tuning function among cardiac functions exhibits abnormality (stimulant genesis abnormality and stimulant conduction abnormality), and includes, for example, sinus arrhythmia, premature beat, atrial fibrillation, paroxysmal supraventricular tachycardia, sinoatrial block, atrioventricular block and the like. The compounds according to the present invention are specifically effective for atrial fibrillation among arrhythmia.
The xe2x80x9cneuralgiaxe2x80x9d in the specification of the present application is dolorific symptom (true and sequential) derived from nerve, and means pain which occurs in the running path of nerve or distribution region thereof. For example, it includes affections such as diabetic neuralgia, HIV neuralgia, postherpetic neuralgia, trigeminal neuralgia, stump pain, postspinal injury pain, thalamic pain, poststroke pain and the like. xe2x80x9cAnalgesicxe2x80x9d means a drug which mitigates or removes pain by changing the perception of rociceptive stimuli without causing anesthetic condition and unconsciousness.
The xe2x80x9cHalogen atomxe2x80x9d used in the specification of the present application refers to atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d used in the specification of the present application refers to an alkyl group having 1 to 6 carbon atoms, and examples thereof include linear or branched alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-ethylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl, 2-ethylbutyl group, 2-methylpentyl group, and 3-methylpentyl group.
The xe2x80x9cC2-6 alkenyl groupxe2x80x9d used in the specification of the present application refers to an alkenyl group having 2 to 6 carbon atoms, and examples thereof include linear or branched alkenyl groups such as vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group and 1,6-hexanedienyl group.
The xe2x80x9cC2-6 alkynyl groupxe2x80x9d used in the specification of the present application refers to an alkynyl group having 2 to 6 carbon atoms, and examples thereof include linear or branched alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group and 1,6-hexanediynyl group.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d used in the specification of the present application refers to a xe2x80x9cC1-6 alkyloxy groupxe2x80x9d in which oxygen atom is bound to a group having the same meaning as the C1-6 alkyl group in the above definition, and examples thereof include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, sec-pentyloxy group, n-hexoxy group, isohexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group etc.
The xe2x80x9cC1-6 alkenyloxy groupxe2x80x9d used in the specification of the present application refers to a group in which an oxygen atom is bound to a group having the same meaning as the C1-6 alkenyl group in the above definition, and examples of a preferable group include vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1,3-hexanedienyloxy group, 1,6-hexanedienyloxy group etc.
Examples of the xe2x80x9cC1-6 alkylthio groupxe2x80x9d used in the specification of the present application include, for example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group, 1-ethylpropylthio group, 2-ethylpropylthio group, n-hexylthio group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-ethylpropylthio group, 1,1,2-trimethylpropylthio group, 1-propylpropylthio group, 1-methylbutylthio group, 2-methylbutylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 2-ethylbutylthio group, 2-methylpentylthio group, 3-methylpentylthio group.
The xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d used in the specification of the present application refers to a cycloalkyl group in which the ring is formed by 3 to 8 carbon atoms, and examples thereof include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group etc. Further, the xe2x80x9cC3-8 cycloalkane groupxe2x80x9d used in the specification of the present application refers to a ring which corresponds to the above-mentioned C3-8 cycloalkyl group.
The xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d used in the specification of the present application refers to a cycloalkenyl group in which the ring is formed by 3 to 8 carbon atoms, and for example, groups represented by the formula: 
are mentioned.
Examples of the xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d used in the specification of the present application refers to mono-cyclic, di-cyclic or tri-cyclic C6-14 aromatic hydrocarbon cyclic groups such as phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, hepthalenyl group, biphenyl group, indathenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, anthracenyl group, cyclopentacyclooctenyl group and benzocyclooctenyl group.
The xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d used in the specification of the present application means a mono-cyclic, di-cyclic or tri-cyclic 5- to 14-membered aromatic heterocyclic group containing any one or more hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and the examples thereof include (i) aromatic heterocyclic groups containing nitrogen such as pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthylidinyl group, quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenacinyl group, imidazopyridinyl group, imidazopyrimidinyl group, a pyrazolopyridinyl group and pyrazolopyridinyl group; (ii) aromatic heterocyclic groups containing sulfur such as thienyl group and benzothienyl group; (iii) aromatic heterocyclic groups containing oxygen such as furyl group, pyranyl group, cyclopentapyranyl group, benzofuranyl group and isobenzofuranyl group; (iv) aromatic heterocyclic groups containing 2 or more different kinds of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, benzooxazolyl group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group and pyridoxazinyl group.
The xe2x80x9c5- to 14-membered non-aromatic heterocyclic ringxe2x80x9d used in the specification of the present application means a mono-cyclic, di-cyclic or tri-cyclic 5- to 14-membered non-aromatic heterocyclic ring containing any of one or more of hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and the examples thereof include pyrrolidine, pyrroline, piperidine, piperazine, imidazoline, pyrazolidine, imidazolidine, morpholine, tetrahydrofuran, tetrahydropyran, aziridine, oxirane, oxathiorane, pyridone ring, and condensed rings such as phthalimide ring and succinimide ring.
The xe2x80x9chydrocarbon groupxe2x80x9d used in the specification of the present application specifically refers to a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl or a C3-8 cycloalkenyl group, and the respective meanings are as described above.
In the compound represented by the above formula (I) according to the present invention, a particularly preferable aspect of each group are as follows.
In a group represented by the formula: 
(wherein R1, R2 and R3 have the same meanings as defined in the above claim 1) indicated by A in the above formula (I), the preferable atom of the xe2x80x9chalogen atomxe2x80x9d indicated by R1 includes fluorine atom, chlorine atom and bromine atom, and fluorine atom and chlorine atom are more preferable.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d in the xe2x80x9cC1-6 alkyl group which may be substitutedxe2x80x9d shown by the above-mentioned R1 or R2 is preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group etc. Further, the xe2x80x9cC2-6 alkenyl groupxe2x80x9d in the xe2x80x9cC2-6 alkenyl group which may be substitutedxe2x80x9d shown by R1 or R2 is preferably vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group etc. Further, the xe2x80x9cC2-6 alkynyl groupxe2x80x9d in the xe2x80x9cC2-6 alkynyl group which may be substitutedxe2x80x9d shown by the above R1 or R2is preferably ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group etc.
The xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d in the xe2x80x9cC3-8 cycloalkyl group which may be substitutedxe2x80x9d by the above-mentioned R1 or R2 is preferably cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group etc. Further, the xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d in the xe2x80x9cC3-8 cycloalkenyl group which may be substitutedxe2x80x9d shown by R1 or R2is preferably cyclobutenyl group, cyclopentenyl group, cyclohexenyl group etc.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d in the xe2x80x9cC1-6 alkoxy group which may be substitutedxe2x80x9d shown by the above-mentioned R1 or R3 is preferably methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec -butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, sec-pentyloxy group, n-hexoxy group, isohexoxy group etc. Further, the xe2x80x9cC2-6 alkenyloxy groupxe2x80x9d in the xe2x80x9cC2-6 alkenyloxy group which may be substitutedxe2x80x9d shown by the above-mentioned R3 is preferably vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1,3-hexanedienyloxy group, 1,6-hexanedienyloxy group etc.
The xe2x80x9cC1-6 alkylthio groupxe2x80x9d in the xe2x80x9cC1-6 alkylthio group which may be substitutedxe2x80x9d shown by the above-mentioned R1 is preferably methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, n-hexylthio group etc.
The xe2x80x9cC1-6 alkylsulfinyl groupxe2x80x9d in the xe2x80x9cC1-6 alkyl sulfinyl group which may be substitutedxe2x80x9d shown by the above-mentioned R1 is preferably methylmethylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, n-pentylsulfinyl group, n-hexylsulfinyl group etc.
The xe2x80x9cC1-6 alkylsulfonyl groupxe2x80x9d in the xe2x80x9cC1-6 alkylsulfonyl group which may be substitutedxe2x80x9d shown by the above-mentioned R1 is preferably methylmethylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group etc.
The xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d in the xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d shown by the above-mentioned R1 or R2 is preferably phenyl group, naphthyl group etc. Further, the xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d in the xe2x80x9c5- to 14-membered aromatic heterocyclic group which may be substitutedxe2x80x9d shown by the above-mentioned R1 or R2 is preferably pyridyl group, pyrazyl group, pyrinidyl group, pyridazinyl group, thienyl group, thiazolyl group, imidazolyl group, furyl group etc.
As the preferable substituent of the amino group in the xe2x80x9camino group which may be substitutedxe2x80x9d shown by the above-mentioned R2, for example, (1) a C1-6 alkyl group which may be substituted (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group etc. which may be substituted, respectively), (2) a C2-6 alkenyl group which may be substituted (for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group etc. which may be substituted, respectively), (3) a C2-6 alkynyl group which may be substituted (for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group etc. which may be substituted, respectively), (4) a C3-8 cycloalkyl group which may be substituted (for example, cyclopropenyl, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group etc. which may be substituted, respectively), (5) a C3-8 cycloalkenyl group which may be substituted (for example, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group etc. which may be substituted, respectively), (6) anacyl group, (7) a carbamoyl group which may be substituted, etc. may be proposed. The relevant amino group may have one or two groups selected from these groups as substituents, and more preferable examples of the amino group includes unsubstituted amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, di(n-propyl)amino group, isopropylamino group, di(isopropyl)amino group etc.
The xe2x80x9cC3-7 cycloalkyloxy groupxe2x80x9d in the xe2x80x9cC3-7 cycloalkyloxy group which may be substitutedxe2x80x9d shown by the above-mentioned R3 is preferably cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group etc. Further, the xe2x80x9cC3-7 cycloalkenyloxy groupxe2x80x9d in the xe2x80x9cC3-7 cycloalkenyloxy group which may be substitutedxe2x80x9d shown by the above-mentioned R3 is preferably cyclobutenyloxy group, cyclopentenyloxy group, cyclohexenyloxy group etc.
The preferable examples of a xe2x80x9csubstituentxe2x80x9d of the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group, the C3-8 cycloalkyl group, the C3-8 cycloalkenyl group, the C1-6 alkoxy group, the C1-6 alkylthio group, the C1-6 alkylsufinyl group, the C1-6 alkylsulfonyl group, the C6-14 aromatic hydrocarbon cyclic group, the 5- to 14-membered aromatic heterocyclic group, the C2-6 alkenyloxy group, the C3-7 cycloalkyloxy group, the C3-7 cycloalkenyloxy group shown by the above-mentioned R1, R2 or R3 and optionally substituted respectively include (1) a hydroxyl group, (2) a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), (3) a cyano group, (4) a nitro group, (5) a C1-6 alkyl group (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group etc.), (6) a C2-6 alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group etc.), (7) a C2-6 alkynyl group (for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group etc.), (8) a C3-8 cycloalkyl group (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group etc.), (9) a C1-6 alkoxy group (for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group etc.), (10) a C1-6 alkylthio group (for example, methylthio group, ethylthio group etc.), (11) a 5- to 14-membered non-aromatic heterocyclic group (for example, piperidyl group, piperazyl group, morpholinyl group etc.), (12) a C6-14 aromatic heterocyclic group (for example, phenyl group, naphthyl group etc.), (13) a 5- to 14-membered aromatic hydrocarbon group (for example, pyridyl group, thienyl group, furyl group, thiazolyl group etc.), (14) an amino group which may be substituted (for example, amino group which may be substituted with one or two groups selected from a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, an acyl group, carbamoyl group which may be substituted, a C1-6 alkyl sulfonyl group etc. (for example, unsubstituted amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, di(n-propyl)amino group, isopropylamino group, di(isopropyl) amino group etc.), or the substituents are bound together to form a nitrogen-containing cyclic group which contains the nitrogen atoms to which they bound). It may have one or more groups selected from these groups, as the substituent.
Examples of the more preferable group as the above-mentioned R1 include a hydrogen atom or a halogen atom (for example, fluorine atom, chlorine atom, bromine atom etc.) Further, examples of the more preferable group as R2 include a hydrogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy C1-6 alkyl group, a C3-8 cycloalkyl C1-6 alkyl group, an aralkyl group (for example, benzyl group, phenethyl group etc.), a mono(C1-6 alkyl)amino C1-6 alkyl group and a di(C1-6 alkyl) aminoalkyl group, and a hydrogen atom is most preferable. Further, examples of the more preferable group as R3 include a C1-6 alkoxy group which may be optionally substituted, and methoxy group is most preferable.
In the compound represented by the above formula (I) according to the present invention, a preferable aspect of the ring A is a ring represented by the formula: 
wherein R1, R2 and R3 have the same meanings as defined in the above-mentioned claim 1. Particularly, a ring represented by the formula: 
is preferable.
Examples in xe2x80x9cC1-6 alkylene group which may be substitutedxe2x80x9d, xe2x80x9cC2-6 alkenylene group which may be substitutedxe2x80x9d or xe2x80x9cC2-6 alkynylene group which may be substitutedxe2x80x9d shown by W in the above formula (I) include a group which may be optionally substituted and represented by the formula xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94. Further, examples of the xe2x80x9csubstituentxe2x80x9d of the C1-6 alkylene group, C2-6 alkenylene group and C2-6 alkynylene group include a hydroxyl group, a halogen atom, a cyano group, a C6-14 aromatic hydrocarbon cyclic group (for example, phenyl group etc.), a 5- to 14-membered aromatic heterocyclic group (for example, pyridyl group, thienyl group, furyl group etc.) etc., and a hydroxyl group and a cyano group are preferable.
Examples of the preferable group as W in the above formula (I) include a group which may be optionally substituted and represented by the formula xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or a group represented by the formula xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94(CH2)3xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x80x94CHxe2x80x94O, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94(CH2)3xe2x80x94SO2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94SO2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94(CH2)3xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94(CH2)3xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94NHxe2x80x94SO2xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94NHxe2x80x94SO2xe2x80x94, and a group represented by the formula xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 etc. are more preferable.
Preferable examples of the xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d in a xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d shown by Z in the above formula (I) include phenyl group, naphthyl group (for example, 1-naphthyl group, 2-naphthyl group etc.), azulenyl group, hepthalenyl group etc.
Examples of a preferable group as the xe2x80x9c5- to 14-membered aromatic heterocyclic group which may be substitutedxe2x80x9d shown by Z in the above formula (I) include pyrrolyl group, pyridyl group, thienyl group, pyridazyl group, pyrimidyl group, pyrazyl group, imidazolyl group, pyrazolyl group, indolyl group, quinolyl group, quinazolyl group, thiazolyl group, benzothienyl group etc.
When Z in the above formula (I) is a xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d or a xe2x80x9c5- to 14-membered aromatic heterocyclic group which may be substitutedxe2x80x9d, the xe2x80x9csubstituentxe2x80x9d includes one or more groups selected from (1) a hydroxyl group, (2) a halogen atom (for example, fluorine atom, chlorine atom and a bromine atom), (3) nitrile group, (4) a hydrocarbon group which may be substituted with one or more groups selected from (i) a halogen atom, (ii) a C6-14 aromatic hydrocarbon cyclic group (phenyl group, naphthyl group) which may be substituted with a halogen atom (for example, fluorine atom and chlorine atom), (iii) a 5- to 14-membered aromatic heterocyclic group (for example, pyridyl group, thienyl group, furyl group, thiazolyl group etc.) which may be substituted with a halogen atom (for example, fluorine atom, chlorine atom etc.), (iv) a C1-6 alkylsulfonyl group etc., such as a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group, (5) a C1-6 alkoxy group (methoxy group, ethoxy group, n-propoxy group, isopropoxy group) which may be substituted with one or more of groups selected from (i) a hydroxyl group, (ii) a halogen atom (for example, fluorine atom, chlorine atom etc.), (iii) a C1-6 alkoxy group, (iv) a sulfonyl group substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group), (v) an amino group substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group) etc., (6) a C3-7 cycloalkyloxy group which may be substituted with (i) a hydroxyl group, (ii) a halogen atom (for example, fluorine atom, chlorine atom etc.), (iii) a C1-6 alkoxy group, (iv) a sulfonyl group substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group)., (v) an amino group substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group) etc., (7) a C6-14 aryloxy group (for example, phenoxy group) which may be substituted with a halogen atom (for example, fluorine atom, chlorine atom etc.), (8) a heteroaryloxy group (for example, pyridyloxy group, thienyloxy group, furyloxy group etc.) which may be substituted with a halogen atom (for example, fluorine atom, chlorine atom etc.), (9) a hydrocarbonthio group (for example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group etc.) which may be substituted with a group selected from (i) a hydroxyl group, (ii) a halogen atom (for example, fluorine atom, chlorine atom etc.), (iii) a C1-6 alkoxy group, (iv) a sulfonyl group substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group) and (v) an amino group which may be substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group), (10) an acyl group represented by the formula xe2x80x94COxe2x80x94N(R6)R7 (wherein R6 and R7 are the same as or different from each other and each indicates (i) a hydrogen atom or (ii) a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group) which may be substituted with a halogen atom (for example, fluorine atom, chlorine atom etc.), or R6 and R7 may be bound together to form a 3- to 7-membered nitrogen-containing non-aromatic heterocyclic ring (for example, piperidine, piperazine, morpholine ring etc.) which contains one or two atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom), (11) a 5- to 14-membered aromatic group (for example, phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, thiazolyl group etc.) which may be substituted with a group selected from (i) a hydroxyl group, (ii) a halogen atom (for example, fluorine atom, chlorine atom etc.), (iii) a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group) which may be substituted with a halogen atom (for example, fluorine atom, chlorine atom etc.), (iv) a C1-6 alkoxy group (methoxy group, ethoxy group, n-propoxy group, isopropoxy group etc.) and (v) a C1-6 alkoxy group (methoxy group, ethoxy group, n-propoxy group, isopropoxy group etc.) substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group) which may be substituted with a halogen atom (for example, fluorine atom, chlorine atom etc.), (12) a 3 to 8-membered non-aromatic heterocyclic group (piperidyl group, piperazyl group, morpholinyl group etc.) which contains one or two atoms selected from nitrogen atom, sulfur atom and an oxygen atom, (13) a sulfonyl group substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group), (14) a sulfonamide group which may be substituted with a hydrocarbon group (a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group), and (15) a C1-4alkylenedioxy group (for example, methylenedioxy group, ethylenedioxy group and propylenedioxy group). For example, a hydroxyl group, nitrile group, a halogen atom (fluorine atom, chlorine atom, blomide atom), methyl group, ethyl group, n-butyl group, trifluoromethyl group, methoxy group, ethoxy group, cyclopropylmethoxy group, 2,2,2-trifluoroethyoxy group, 2-methoxyethoxy group, 2-hydroxyethoxy group, 2-(N,N-dimethylamino)ethoxy group, phenoxy group, phenyl group, imidazolyl group, pyrazolyl group, thiazolyl group, methoxyphenyl group, piperidyl group, piperazyl group, morpholinyl group, N-acetylpiperazyl group, methylsulfonyl group, amino group, trifluoroacetylamino group, methylsulfonyl group, ethylsulfonyl group, alkylenedioxy group etc. may be proposed. Here, the xe2x80x9cC1-6 alkyl groupxe2x80x9d, xe2x80x9cC2-6 alkenyl groupxe2x80x9d, xe2x80x9cC2-6 alkynyl groupxe2x80x9d, xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d and xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d listed as a xe2x80x9chydrocarbon groupxe2x80x9d have the same meanings as defined above, respectively.
In the group represented by the formula xe2x80x94N(R4)R5 (wherein R4 and R5 have the same meanings as defined above) shown by Z in the above formula (I), the xe2x80x9cC1-6 alkyl groupxe2x80x9d in the xe2x80x9cC1-6 alkyl group which may be substitutedxe2x80x9d shown by R4 or R5 is preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group etc., the xe2x80x9cC2-6 alkenyl groupxe2x80x9d in the xe2x80x9cC2-6 alkenyl group which may be substitutedxe2x80x9d is preferably vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group etc., and the xe2x80x9cC2-6 alkynyl groupxe2x80x9d in the xe2x80x9cC2-6 alkynyl group which may be substitutedxe2x80x9d is preferably ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group etc. Further, the xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d in the xe2x80x9cC3-8 cycloalkyl group which may be substitutedxe2x80x9d shown by R4 or R5 is preferably cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group etc., and the xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d in the xe2x80x9cC3-8 cycloalkenyl group which may be substitutedxe2x80x9d is preferably cyclobutenyl group, cyclopentenyl group, cyclohexenyl group etc. Further, the xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d in the xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may be substitutedxe2x80x9d shown by R4 or R5 is preferably phenyl group, naphthyl group etc. The xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d in the xe2x80x9c5- to 14-membered aromatic heterocyclic group which may be substitutedxe2x80x9d is preferably pyridyl group, pyrazyl group, pyrimidyl group, pyridazinyl group, thienyl group, thiazolyl group, imidazolyl group, furyl group etc.
When the above-mentioned R4 or R5 are the same as or different from each other and each is a C1-6 alkyl group which may be substituted, a C2-6 alkenyl group which may be substituted, a C2-6 alkynyl group which may be substituted, a C3-8 cycloalkyl group which may be substituted or a C3-8 cycloalkenyl group which may be substituted, preferable examples of the xe2x80x9csubstituentxe2x80x9d include (1) a hydroxyl group, (2) a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), (3) a C1-6 alkoxy group which may be substituted (for example, a methoxy group, a methoxy group, ann-propoxy group, anisopropoxy group, an n-butoxy group, a tert-butoxy group etc. which may be substituted with a halogen atom, respectively), (4) a C6-14 aromatic hydrocarbon cyclic group which may be substituted (for example, a 5- to 14-membered aromatic group which may be substituted with any one or more groups selected from a hydroxyl group, a halogen atom, a hydrocarbon group which may be substituted with a halogen atom, a C1-6 alkoxy group which may be substituted with a halogen atom, and a 5- to 14-membered aromatic group), (5) a 5- to 14-membered aromatic heterocyclic group which may be substituted (for example, a 5- to 14-membered aromatic group which may be substituted with any one or more of groups selected from a hydroxyl group, a halogen atom, a hydrocarbon group which may be substituted with a halogen atom, a C1-6 alkoxy group which may be substituted with a halogen atom and a 5- to 14-membered aromatic group, etc.) etc. Specific examples thereof include one or two groups selected from ethyl group, 2-methylpropyl group, isopropyl group, n-pentyl group, n-octyl group, tert-butyl group, hydroxy-tert-butyl group, cyclohexyl group, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 2,2,2-trifluoroethyl group, morpholylethyl group, hydroxyethyl group, hydroxypropyl group, 5-phenylpentyl group, 2-propyn-1-yl group, 1,2-dimethylpropyl group, 2-ethyl-n-butyl group, benzyl group, phenethyl group, a halogenated benzyl group, hydroxybenzyl group, o-phenylbenzyl group, methyl sulfonylbenzyl group, methylsulfonylaminobenzyl group, pyridylmethyl group, furylmethyl group, N-methylpyrolylethyl group, diphenylmethyl group, methylenedioxyphenylmethyl group, methoxypyridylmethyl group and dimethylaminomethyl group.
When the above-mentioned R4 or R5 are the same as or different from each other and each is an optionally substituted C6-14 aromatic hydrocarbon cyclic group 5- to 14-membered aromatic heterocyclic group, the preferable examples of the xe2x80x9csubstituentxe2x80x9d include (1) hydroxy group, (2) a halogen atom, (3) nitrile group, (4) a hydrocarbon group which may be substituted with such as a halogen atom, a 5- to 14-membered aromatic group which may be substituted with a halogen atom and a C1-6 alkylsulfonyl group, (5) a C1-6 alkoxy group which may be substituted with such as a hydroxyl group, a halogen atom, a C1-6 alkoxy group, a sulfonyl group substituted with a hydrocarbon group and an amino group which may be substituted with a hydrocarbon group, (6) a C3-7 cycloalkyloxy group which may be substituted with such as a hydroxyl group, a halogen atom, a C1-6 alkoxy group, a sulfonyl group substituted with a hydrocarbon group and an amino group which may be substituted with a hydrocarbon group, (7) a (C6-10 aryl)-oxy group which may be substituted with a halogen atom etc., (8) a (5- to 14-membered heteroaryl)-oxy group which may be substituted with a halogen atom etc., (9) a hydrocarbon-thio group which may be substituted with a group selected from a hydroxyl group, a halogen atom, a C1-6 alkoxy group, a sulfonyl group substituted with a hydrocarbon group and an amino group which may be substituted with a hydrocarbon group, (10) an acyl group represented by the formula xe2x80x94COxe2x80x94N(R12)R13 (wherein R12 and R13 are the same as or different from each other and each indicates a hydrogen atom or a hydrocarbon group which may be substituted with a halogen atom, and further, in the formula xe2x80x94COxe2x80x94N(R12)R13, R12 and R13 may be bound together to form a 3- to 7-membered nitrogen-containing non-aromatic heterocyclic ring containing one or two atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom), (11) a 5- to 14-membered aromatic group which may be substituted with a group selected from a hydroxyl group, a halogen atom, a hydrocarbon group which may be substituted with a halogen atom and a hydrocarbon C1-6 alkoxy group which may be substituted with a halogen atom, (12) a 3 to 7-membered non-aromatic heterocyclic group which contains one or two atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, (13) a sulfonyl group substituted with a hydrocarbon group, (14) a sulfoneamide group which may be substituted with a hydrocarbon group, (15) a C1-2 alkylenedioxy group, etc.
The xe2x80x9cC1-6 aliphatic acyl groupxe2x80x9d shown by the above-mentioned R4 or R5 means a carbonyl group which was substituted with groups such as a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy-C1-6 alkyl group, a C1-6 alkoxy group, a C6-14 aryl group, a 5- to 14-membered aromatic heterocyclic group etc., and as the preferable examples, acetyl group, ethylcarbonyl group etc. are listed.
In the above formula (I), Z may indicate a 3- to 8-membered nitrogen-containing cyclic group obtained by R4 and R5 in the formula xe2x80x94N(R4)R5 bound together, and the preferable examples of the group include piperidyl group, piperazyl group, morpholinyl group etc.
In the above formula (I), the symbol l indicates an integer of 0, 1, 2, 3, 4, 5 or 6, an integer of 1 to 3 is preferable, an integer of 1 or 2 is more preferable, and an integer of 1 is further preferable.
As the more preferable aspect of the compound represented by the above formula (I) according to the present invention, a compound represented by the formula: 
(wherein R1, R2, W, Z and l have the same meanings as defined above, respectively), a salt thereof or a hydrate of them may be proposed, and as the particularly preferable aspect, a compound represented by the formula: 
(wherein R1, W and Z have the same meanings as defined in the above claim 1), a salt thereof or a hydrate of them may be proposed.
The xe2x80x9csaltxe2x80x9d according to the specification of the present application is not specifically limited so far as it forms a salt with a compound according to the present invention and is pharmacologically acceptable. Preferably, a salt of a hydrogen halide acid (for example, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), an inorganic acid salt (for example, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate etc.), an organic acid salt (for example, acetate, trifluoroacetate, oxalate, maleate, tartarate, fumarate, citrate etc.), a salt of an organosulfonic acid (for example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate etc.), a salt of amino acid (for example, aspartate, glutamate etc.), a quaternary ammonium salt, an alkali metal salt (for example, sodium salt, potassium salt etc.), an alkali earth metal salt (for example, magnesium salt, calcium salt etc.), etc. may proposed. Hydrogen chloride, oxalate, trifluoroacetate etc. are more preferable.
The typical process for producing the compound represented by the above formula (I) according to the present invention is shown below. 
In the formula, R1, W, Z and l have the same meanings as defined above; and L1 indicates a leaving group (for example, a halogen atom, tosylate etc.) or an aldehyde group. The compound (I)-1 according to the present invention can be produced by condensing a piperidine derivative (II) with a pyridine derivative (III) in a solvent by the reductive amination method, or by condensing them in the presence of a base. When the reductive amination method is used, the solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1-methylpyrrolidone, acetonitrile etc. are preferable. As the reducing agent, metal hydrides such as sodium borohydride, sodium triacetoxyborohydride etc. can be used. Further, a catalytic reduction method which conventionally used can be carried out. The amount of the reducing agent used is 1 to 5 equivalents to a raw material. The reaction temperature is conventionally from xe2x88x9250xc2x0 C. to are flux temperature of the solvent, and preferably about 0 to about 25xc2x0 C. All of the organic solvents which are inert to reaction can be used in case of the condensation in the presence of a base, and for example, benzene, dichloromethane, acetonitrile, THF, dioxane, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone etc. may be proposed. The base used is not specifically limited, but sodium hydride, potassium, tert-butoxide, lithium diisopropylamide, potassium carbonate, sodium hydroxide etc. are preferable. The amount of the base used is 1 to 10 equivalent to a raw material. The reaction temperature is conventionally from xe2x88x9250xc2x0 C. to are flux temperature of the solvent, and preferably 20 to 80xc2x0 C.
The production process is shown below when W is a xe2x80x9chydrocarbon chain which may be substitutedxe2x80x9d in the above formula (I). 
In the formula, R1 and l have the same meanings as defined above; Z1 indicates a 5- to 14-membered aromatic group which may be substituted; and g indicates 0, 1 and 2. The pyridylpiperidine derivative (I)-1-1 according to the present invention can be produced by carrying out Wittig reaction or an analogous reaction to the piperidine aldehyde derivative (IV) in an organic solvent. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, ethyl acetate, dimethylformamide, dimethyl sulfoxide, toluene, benzene etc. are preferable. The Wittig reagent which is commercially available is bought and those which are not commercially available can be easily prepared according to a conventional method. The amount of the Wittig reagent used is 1 to 2 equivalents to a raw material. Examples of the base used are preferably sodium hydride, potassium tert-butoxide, potassium methoxide, sodium ethoxide, lithium diisopropylamide, diazabicycloundecene, n-butyl lithium, sodium hydroxide etc. The amount of the base used is 1 to 2 equivalents to a raw material. The reaction temperature is conventionally from xe2x88x9270xc2x0 C. to a reflux temperature of the solvent, and preferably about xe2x88x9240 to about 60xc2x0 C. 
In the formula, R1 and l have the same meanings as defined above, Z2 indicates a 5- to 14-membered aromatic group which may be substituted; and L2 indicates a leaving group (for example, a halogen atom, triflate etc.). The compound (I)-1-2 according to the present invention can be produced by reacting (VI) (for example, aryl halide, aryl triflate etc.) to an alkynylpiperidine derivative (V) in a solvent in the presence of a catalyst. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, toluene, benzene, 1-methylpyrrolidone etc. are preferable. The present reaction can be carried out in the presence of a reagent of either of tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium(II) in a catalytic amount, cupric iodide and a tertiary amine. As the tertiary amine used, for example, triethylamine, diisopropylethylamine, dimethylaniline, diazabicycloundecene etc. are preferable. The amount of the catalyst used is about 0.001 to about 0.1 mol % based on a raw material. The reaction is carried out under a nitrogen flow, and the reaction temperature is conventionally from xe2x88x9220xc2x0 C. to a reflux temperature of the solvent, and preferably about 80 to about 140xc2x0 C. 
In the formula, R1, l, g and Z1 have the same meanings as defined above, and h indicates an integer of any one of 1 to 3. The compound (I)-1-3 according to the present invention can be produced by carrying out the catalytic reduction of the pyridylpiperidine derivative (I)-1-1 obtained in the reaction 2. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, ethanol, methanol etc. are preferable. In the present reaction, a good result can be also obtained by adding an appropriate amount of an acid to the reaction solution. As the catalyst used, palladium carbon (Pdxe2x80x94C), Raney-Nickel, platinum oxide (PtO2) etc. are preferable. The reaction temperature is generally from 0xc2x0 C. to 120xc2x0 C., and preferably about 25xc2x0 C. The hydrogen pressure during reduction is 1 to 140 kg/cm2, and preferably 1 to 3 kg/cm2. 
In the formula, R1, l and Z2 have the same meanings as defined above. The compound (I)-1-4 according to the present invention can be produced by carrying out the catalytic hydrogenation of (I)-1-2 obtained in the xe2x80x9creaction 3xe2x80x9d. The present reaction can be carried out under the same condition as in the xe2x80x9creaction 4xe2x80x9d. 
In the formula, R1, l, g, h and Z1 have the same meanings as defined above. The compound (I)-1-3 according to the present invention can be produced by reacting a Wittig reagent with the piperidinealdehyde derivative (IV) in the presence of a base and carrying out the catalytic hydrogenation of the pyridylpiperidine derivative (I)-1-1 obtained, without separation. The Wittig reaction can be carried out according to the method described in the reaction 2, and the catalytic hydrogenation can be carried out according to the method described in the xe2x80x9creaction 4xe2x80x9d. 
In the formula, R1, l, i and Z1 have the same meanings as defined above; L3 indicates a leaving group (for example, a halogen atom, triflate etc.), and Q1 and Z3 indicate a 5- to 14-membered aromatic group which may be substituted. The compound (I)-1-5 according to the present invention can be produced in the presence of a palladium catalyst from the compound (I)-1-1-i in which Z1 is represented by Z3xe2x80x94L3 among the compound (I)-1-1 obtained in the xe2x80x9creaction 2xe2x80x9d. As the aryl metal compound used for the reaction, for example, aryltributyltin, aryl boric acid, other conventionally-used arylalkoxyborane, arylalkylborane, etc. are listed. The amount of the aryl metal compound used is conventionally 1 to 5 equivalents to a raw material, and preferably about 2 equivalents. As the catalyst used, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)-palladium(II) etc. are mentioned. The amount of the catalyst used is about 0.05 mol % to a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, tetrahydrofuran (THF), dioxane, diethylene glycol dimethyl ether, toluene, benzene etc. are preferable. When aryl boric acid is used as the aryl metal compound, aqueous sodium carbonate, methanol and a mixture of organic solvents are preferable. The reaction temperature is conventionally from room temperature to 150xc2x0 C., and preferably from 80 to 130xc2x0 C. The compound (I)-1-5 obtained by the present production process can be used as a raw material in the reaction 4. 
In the formula, R1 and l have the same meanings as defined above; j indicates an integer of any one of 1 to 3; L4 indicates a leaving group (for example, a halogen atom, tosylate, triflate etc.); and Q2 indicates a substituent (for example, a C1-6 alkoxy group, an alkylamino group etc.). The compound (I)-1-8 according to the present invention can be also produced by further reacting the pyridine derivative (I)-1-7 which has the eliminating group L4 at 2-position of the aromatic groups represented by Z and Z1 among the compound obtained in the above-mentioned reactions 1 or 4, with a nucleophile. As the nucleophile used, alkoxides obtained by reacting bases such as sodium hydride, potassium tert-butoxide, sodium metal, lithium metal and sodium diisopropylamide with alcohols such as methanol, ethanol and dimethylaminoethanol, and additionally, primary or secondary amines such as piperidine and morpholine are preferable. When an amine is used as the nucleophile, a good result can be obtained even if a base having a weak nucleophilic property such as potassium carbonate, diisopropylethylamine and triethylamine coexist. The amount of the nucleophile used is 1 to a greatly excessive amount for a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidone etc. are preferable. When an alkoxide is used as the nucleophile, an alcohol can be used as the solvent. The reaction temperature is generally from 0 to 200xc2x0 C., and preferably from 100 to 170xc2x0 C. 
In the formula, R1, l and g have the same meanings as defined above; j indicates an integer of anyone of 1 to 3, and Z4 indicates a 5- to 14-membered aromatic group which may be substituted. The compound (I)-1-9 according to the present invention can be produced by reacting an aryl metal or an aryl metal halide with the aldehyde derivative (IV) by 1,2-addition to give an intermediate and oxidizing it. The aryl metal or aryl metal halide used in the 1,2-addition reaction is bought when it is commercially available, and can be prepared according to a conventional method to be used when it is not commercially available. The amount of the aryl metal or aryl metal halide used is 1 to 5 equivalents to a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, toluene, benzene etc. are preferable. The reaction temperature is generally from xe2x88x9278 to 0xc2x0 C. As an oxidant used for oxidation reaction, for example, Swern oxidant which is adjusted by sulfur trioxide-pyridine complex, chlorochromic acid pyridinium, manganese dioxide, di(chromic acid)pyridinium, oxalyl chloride-dimethyl sulfoxide etc. are preferable. The solvent used in the oxidation reaction is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, acetonitrile, ethyl acetate, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone etc. are preferable. The reaction temperature is generally from 0xc2x0 C. to a reflux temperature of the solvent. 
In the formula, R1, l and Z4 have the same meanings as defined above; and k indicates an integer of any of 0 to 2. The compound (I)-1-9 according to the present invention can be produced by reacting an aryl metal or an aryl metal halide with the amide derivative (VII). The aryl metal or aryl metal halide used is bought when it is commercially available, and can be prepared according to a conventional method to be used when it is not commercially available. The amount of the aryl metal or aryl metal halide used is about 1 to about 2 equivalents to a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, toluene, benzene etc. are preferable. The reaction temperature is conventionally from xe2x88x9278 to 0xc2x0 C. 
In the formula, R1, R4, R5 and l have the same meanings as defined above; and m indicates an integer of any one of 0, 1 and 2. The compound (I)-1-10 according to the present invention can be produced by carrying out the condensation reaction of the carboxylic acid derivative (VIII) and an amine represented by the formula NH(R4)R5 in an organic solvent. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, dimethylformamide, dimethyl sulfoxide, ethanol, methanol etc. are preferable. As the condensation reaction, reactions conventionally carried out can be used. For example, a DCC method, a DCC-HOBt method, a DCC-HOSu method, and an improved method in accordance with these methods (for example, a WSC-HOBt method) etc. can be used. The amount of a condensing agent used is 1 to 5 equivalents to the raw material (VIII). Further, after a carboxylic acid-piperidine derivative is made as a reactive derivative conventionally used, it can be also carried out by reacting the derivative with an amine. As there active derivative used, for example, an acid chloride obtained by treating with thionyl chloride etc., an acid anhydride introduced by reacting isobutyloxycarbonyl chloride (IBCF), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), ethyl chlorocarbonate etc. with the carboxylic acid derivative (VIII), those which is obtained by converting the carboxylic acid derivative (VIII) into an acid azide by using diphenylphosphoryl azide (DPPA), etc. are preferable. Further, they can be introduced to active esters such as p-nitrophenylester (ONp) and N-hydroxysuccinimide (ONSu). The compound (I)-1-10 according to the present invention can be obtained by reacting the reactive derivative with the amine NH(R4)R5 in an organic solvent. 
In the formula R1, W, Z and l have the same meanings as defined above. The pyridonepiperidine derivative (I)-2 being the compound according to the present invention can be produced by hydrolyzing the pyridylpiperidine derivative (I)-1. The present reaction can be carried out by interacting 2 equivalents to a greatly excessive amount of an appropriate acid in water or a mixed solvent of water and organic solvents such as methanol, ethanol, dioxane and tetrahydrofuran. As the acid used, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid etc. are preferable, and an acid may be generated in the reaction system by adding thionyl chloride in an alcohol solvent. The reaction temperature is generally from a room temperature to a reflux temperature. Further, the present reaction can be carried out by interacting 2 equivalents to a greatly excessive amount of trimethylsilyl iodide or trimethylsilane chloride-sodium iodide in an organic solvent such as dichloromethane, chloroform, dichloroethane and acetonitrile. The reaction temperature is generally from xe2x88x9278xc2x0 C. to a reflux temperature of the solvent and preferably from xe2x88x9220xc2x0 C. to room temperature. 
In the formula, R1, W, Z and l have the same meanings as defined above; and L5 indicates a leaving group (for example, a halogen atom etc.). The pyridonepiperidine derivative (I)-2 being the compound according to the present invention can be produced by hydrolyzing the 2-substituted pyridine derivative (X). The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, tert-butanol etc. are preferable. The base used for hydrolysis reaction is not specifically limited, but potassium tert-butoxide is preferable. The reaction temperature is generally from room temperature to a reflux temperature of the solvent, and preferably from 100 to 140xc2x0 C. 
In the formula, R1, W, Z and l have the same meanings as defined above. Further, TBSO- in the formula means tert-butyldimethylsilyl ether. The compound (I)-2 according to the present invention can be produced by condensing the piperidine derivative (II) and the pyridine derivative (X) in an organic solvent by reductive amination. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, dimethylformamide, dimethyl sulfoxide etc. are preferable. As the reducing agent used, for example, metal hydrides such as sodium borohydride and triacetoxy sodium boronhydride are preferable. Further, a catalytic reduction method which conventionally used can be carried out. The amount of the metal halide used is 1 to 5 equivalents to a raw material. In the present reaction, the tert-butyldimethylsilyl group is naturally deprotected by the acidity of the silica gel used at a step of purifying the product. The reaction temperature is generally from xe2x88x9250xc2x0 C. to a reflux temperature of the solvent, and preferably about 0 to about 25xc2x0 C. 
In the formula, R1, R2, W, Z and l have the same meanings as defined above; and L2 indicates a leaving group (for example, a halogen atom, a tosylate, a mesylate etc.). The N-substituted pyridonepiperidine derivative (I)-3 being the compound according to the present invention can be produced by interacting a compound R2L2 with the pyridonepiperidine derivative (I)-2 together with an appropriate base in an organic solvent. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, ethanol, methanol etc. are preferable. As the base used, for example, sodium hydride, potassium tert-butoxide, potassium methoxide, lithium diisopropylamide, potassium carbonate, sodium hydroxide etc. are preferable. The amount of the base used is 1 to 10 equivalents to a raw material. The amount of the compound, R2L2 used is 1 equivalent to a greatly excessive amount to a raw material. The reaction temperature is generally from a room temperature to a reflux temperature. 
In the formula, R1, l and g have the same meanings as defined above. The piperidinealdehyde derivative (IV) which is a raw material in the above-mentioned xe2x80x9creactions 2, 4 and 7xe2x80x9d can be produced by oxidizing the alcohol derivative (XI). The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone, ethers such as tetrahydrofuran, dioxane and diethyleneglycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, acetonitrile, toluene etc. are preferable. As oxidation methods used for oxidation reaction, for example, an oxidation method using chlorochromic acid pyridinium, manganese dioxide and di(chromic acid)pyridinium as an oxidant, oxidation methods such as Swern oxidation, Jones oxidation, Corey-Khim oxidation and the like are preferable. The reaction temperature is conventionally from xe2x88x9250xc2x0 C. to a reflux temperature of the solvent. 
In the formula, R1, l and g have the same meanings as defined above; and L7 indicates a leaving group (for example, a halogen atom, tosylate etc.) or an aldehyde group. The pyridylpiperidine derivative (XI) which is a raw material for the above-mentioned xe2x80x9creaction 16xe2x80x9d can be produced by condensing the piperidine derivative (XIII) and the pyridine derivative (XII) by reductive amination, or by condensing them in the presence of a base. The present reaction can be carried out under the same condition as in the above-mentioned xe2x80x9creaction 1xe2x80x9d. The commercially available product of the pyridine derivative (XII) is bought, and those which are not commercially available can be easily prepared according to a conventional method to be used. 
In the formula, R1 and l have the same meanings as defined above; and each of Hal1 and Hal2 indicates the same or different halogen atom. The alkynylpiperidine derivative (V) which is a raw material in the above-mentioned xe2x80x9creaction 3xe2x80x9d can be produced by carrying out the dehalogenation reaction of the olefin derivative (XIV). The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, toluene etc. are preferable. As the base used, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, etc. are preferable. The amount of the base used is 1 to 10 equivalents to a raw material. The reaction temperature is generally from xe2x88x92100 to xe2x88x9250xc2x0 C. 
In the formula, R1, l Hal1 and Hal2 have the same meanings as defined above. The olefin derivative (XIV) which is a raw material in the above-mentioned xe2x80x9creaction 18xe2x80x9d can be produced by interacting the piperidinealdehyde derivative (IV)-1 and carbon tetra halide in the presence of triphenylphosphine. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, 1-methylpyrrolidone, ethers such as tetrahydrofuran (THF), dioxane and diethylene-glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, acetonitrile, toluene etc. are preferable. As the base added, for example, tertiary amines such as triethylamine and diisopropylethylamine are preferable. The amount of the base used is 2 equivalents to a greatly excessive amount to a raw material. The reaction temperature is conventionally from xe2x88x9250 to 80xc2x0 C., and preferably about 0xc2x0 C. 
In the formula, R1 and l have the same meanings as defined above; L8 indicates a leaving group (for example, a halogen atom, tosylate, mesylate, triphlate etc.); Q3 indicates a substituent (for example, a C1-6 alkoxy group, an alkylamino group etc.); and n indicates an integer of 1 to 3. In the pyridonpiperidine derivative (I)-2 obtained in each of the above-mentioned xe2x80x9creactions 13, 14 and 15xe2x80x9d, the compound (1)-2-1 in which Z is a pyridyl group having a leaving group at 2-position can be converted into the compound (I)-2-2 according to the present invention, by being reacted with an appropriate nucleophile. The present reaction can be carried out under the similar condition as in the above-mentioned xe2x80x9creaction 8xe2x80x9d. 
In the formula, R1, l, W and L5 have the same meanings as defined above; and L9 indicates a leaving group (for example, a halogen atom, tosylate etc.) or an aldehyde group. The pyridylpiperidine derivative (IX) which is the raw material for the xe2x80x9creaction 13xe2x80x9d can be produced by condensing the piperidine derivative (II) and the pyridine derivative (XV) in a solvent by reductive amination reaction, or by condensing them in the presence of a base. The present reaction can be carried out under the similar condition as in the xe2x80x9creaction 1xe2x80x9d. The commercially available pyridine derivative (XV) used is bought, and the derivatives which are not commercially available can be easily prepared from a known raw material according to a conventional method to be used. 
In the formula, W and Z each have the same meanings as defined above; and Q4 indicates a group conventionally used for protecting an amino group. The piperidine derivative (II) can be produced by carrying out the deprotection of the piperidine derivative (XVI) which has a protecting group. The deprotection can be carried out under the condition of the deprotection conventionally used. For example, when Q4 is benzyloxycarbonyl group, it can be carried out by a catalytic reduction method using palladium carbon as a catalyst in an organic solvent, and when Q4 is tert-butyloxycarbonyl group, it can be carried out by intereacting an appropriate acid such as hydrochloric acid, sulfuric acid and trifluoroacetic acid in an organic solvent or a mix solvent of water and an organic solvent. Further, when Q4 is benzyl group, it can be carried out by interacting 1-chloroethyl chloroformate and methanol in order in an appropriate organic solvent (for example, halogenated solvents such as dichloromethane). 
In the formula, Z and Q4 have the same meanings as defined above; and p indicates a number of either of 0 or 1. The piperidinealdehyde derivative (XVIII) which is a raw material in the above-mentioned xe2x80x9creaction 22xe2x80x9d can be produced by carrying out the catalytic hydrogenation of the olefin derivative prepared by reacting Wittig reagent to the piperidinealdehyde derivative (XVII) in the presence of a base. The Wittig reaction can be carried out according to the condition of the above-mentioned xe2x80x9creaction 2xe2x80x9d. The commercially available Wittig reagent is bought, and the reagent which is not commercially available can be easily prepared according to a conventional method to be used. The catalytic hydrogenation in the present reaction can be carried out according to the condition of the above-mentioned xe2x80x9creaction 4xe2x80x9d. 
In the formula, R4, R5 and Q4 have the same meanings as defined above; and q indicates an integer of 1 to 2. The amide derivative (XX) which is the raw material for production of the compound according to the present invention can be produced by carrying out the conventional condensation reaction of the carboxylic acid derivative (XIX) and an amine represented by the formula NH(R4)R5 in an organic solvent. The present reaction can be carried out according to the condition of the above-mentioned xe2x80x9creaction 11xe2x80x9d. 
In the formula, Q4 and q have the same meanings as defined above. The carboxylic acid derivative (XIX) as the raw material of the above-mentioned xe2x80x9creaction 24xe2x80x9d can be produced by protecting the nitrogen atom of the piperidine derivative (XXI) by an appropriate group. The present reaction can be carried out according to the condition conventionally used for the protection of an amino group. For example, when Q4 is tert-butoxycarbonyl group (Boc), di-tert-butyl dicarbonate is preferable as a reagent for adding Boc. The amount of the reagent used is 1 to 5 equivalents to a raw material. The reaction of adding Boc can be carried out in a mix solvent of water and organic solvents such as tert-butanol in the presence of a base, and the reaction temperature is generally from 0 to 80xc2x0 C., and preferably from 0 to 25xc2x0 C. 
In the formula, R1, l, g, h and Z4 have the same meanings as defined above; and Z4 indicates a 5- to 14-membered aromatic group which may be substituted. The compound (XXII) according to the present invention can be produced by carrying out the 1,2-addition of an aryl metal to the aldehyde derivative (IV) to give an alcohol intermediate and dehydrating it. The commercially available aryl metal used for the 1,2-addition is bought, and the aryl metals which are not commercially available can be prepared according to a conventional method to be used. The amount of the aryl metal used is 1 to 5 equivalents to a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane, ether and diethylene glycol dimethyl ether, and additionally, toluene, benzene etc. are preferable. The reaction temperature is conventionally from xe2x88x9278 to 0xc2x0 C. As the dehydrating agent used for dehydration reaction, acids such as p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, and acid chlorides such as phosphorous oxychloride and thionyl chloride are preferable. When an acid chloride is used as the dehydrating agent, a good result can be also obtained by coexisting bases such as pyridine, triethylamine and diisopropylethylamine in the reaction system. The reaction can be carried out without a solvent or in an appropriate solvent. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, halogenated hydrocarbons such as dichlolomethane, chloroform and dichloroethane, and additionally, toluene, benzene etc. are preferable. The reaction temperature is generally from xe2x88x9220xc2x0 C. to a reflux temperature of the solvent, and preferably from 0 to 120xc2x0 C. 
In the formula, R1, R2, W, Z and l have the same meanings as defined above. The compound (I)-2 according to the present invention can be produced by condensing the piperidine derivative (II) and the pyridine derivative (YYYY) in a solvent by reductive amination. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane and diethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, and additionally, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1-methylpyrrolidone, acetonitrile etc. are preferable. As the reducing agent, for example, metal hydrides such as sodium borohydride and triacetoxy sodium boronhydride can be used. Further, a catalytic reduction method conventionally used can be carried out. The amount of the reducing agent used is 1 to 5 equivalents to a raw material. The reaction temperature is generally from xe2x88x9250xc2x0 C. to a reflux temperature of the solvent, and preferably about 0 to about 25xc2x0 C. 
In the formula, R1 and l have the same meanings as defined above; X indicates a leaving group (for example, a halogen atom, triflate etc.); and, R1xe2x80x94L indicates an aryl metal compound or an alkyl metal compound. Examples of the aryl metal compound or alkyl metal compound used in the present reaction include, for example, aryl boric acid, aryltributyltin, alkyl boric acid, alkyltributyltin, alkoxyborane derivatives, alkylborane derivatives etc. conventionally used. The amount of the aryl metal compound or alkyl metal compound used is generally 1 to 5 equivalents to a raw material, and preferably about 2 equivalents. As the catalyst used, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium(II) etc. are listed. The amount of the catalyst used is about 0.05 mol % to a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, tetrahydrofuran (THF), dioxane, diethylene glycol dimethyl ether, toluene, benzene, dimethylformamide (DMF), 1-methylpyrrolidone etc. are preferable. When an aryl boric acid or an alkyl boric acid is used as the aryl metal compound or alkyl metal compound, it is preferable to coexist bases such as potassium carbonate, cesium carbonate and sodium carbonate, or an aqueous solution thereof. The reaction temperature is generally from room temperature to a reflux temperature of the solvent, and preferably from 80 to 130xc2x0 C. 
In the formula, R1 and l have the same meanings as defined above; and X indicates a leaving group (for example, a halogen atom, triflate etc.). The compound (XXVI) can be produced from the aldehyde derivative (XXV) under the condition for acetalization conventionally used. For example, it can be obtained by intereacting trimethyl orthoformate, dimethoxypropane etc. in an organic solvent in the presence of a catalyst (for example, p-toluenesulfonic acid) or montmorillonite K-10. 
In the formula, R1 and l have the same meanings as defined above, and X indicates a leaving group (for example, a halogen atom, triflate etc.). The compound (XXVII) can be obtained by reacting a cyan compound with the acetal derivative (XXVI) in the presence of cuprous iodide and a catalyst, and then hydrolyzing the acetal. As the cyanide compound used, for example, sodium cyanide, potassium cyanide, zinc cyanide etc. are mentioned. The amount of the cyanide compound used is conventionally 1 to 5 equivalents to a raw material, and preferably about 2 equivalents. As the catalyst used, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium(II) etc. are mentioned. The amount of the catalyst used is about 0.001 to 0.1 mol % based on a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, tetrahydrofuran (THF), dioxane, diethylene glycol dimethyl ether, toluene, benzene, dimethylformamide (DMF), 1-methylpyrrolidone, acetonitrile, propionitrile, and the like are preferable. The reaction temperature is conventionally from room temperature to a reflux temperature of the solvent, and preferably from 80 to 140xc2x0 C.
The hydrolysis reaction can be carried out under the condition for hydrolysis conventionally used. For example, it can be carried out by interacting an appropriate acid such as hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid in an organic solvent or a mix solvent of water and an organic solvent. 
In the formula, l has the same meaning as defined above. The compound (XXIX) according to the present invention can be produced by reacting the acetal derivative (XXVIII) with an organometallic reagent to be metalated, reacting it with a fluorinating agent and then hydrolyzing the acetal. The metalation reaction can be carried out under the condition for metalation conventionally used. As the organometallic reagent used for the metalation, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium etc. are listed. As the fluorinating agent, for example, N-fluoroimides such as N-fluorobenzenesulfonimide, or N-fluoropyridinium derivatives such as N-fluoro-4-methyl pyridinium-2-sulfonate are listed. The amount of the fluorinating agent used is conventionally 1 to 2 equivalents based on a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane, ether and diethylene glycol dimethyl ether are preferable. The reaction temperature is conventionally from xe2x88x9278 to 0xc2x0 C., and preferably from xe2x88x9278 to xe2x88x9240xc2x0 C.
The hydrolysis reaction can be carried out under the condition for hydrolysis conventionally used. For example, it can be carried out by interacting an appropriate acid such as hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid in an organic solvent or a mix solvent of water and an organic solvent. 
In the formula, l has the same meaning as defined above; and R indicates an aralkyl group. The compound (XXX) according to the present invention can be produced by reacting the acetal derivative (XXVIII) with an organometallic reagent to be metalated, reacting it with an organic sulfur compound, oxydizing the aralkylthio group and then hydrolyzing the acetal. The metalation reaction can be carried out under the conventional condition for metalation. As the organometallic reagent used for the metalation, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium etc. may be proposed. As the organic sulfur compound used for alkylthiolation, for example, disufides such as dimethyl disulfide and diphenyl disulfide, sulfenylchlorides such as phenylsulfenylchloride, etc. may be proposed. The amount of the organic sulfur compound used is conventionally 1 to 2 equivalents based on a raw material. The solvent used is not specifically limited so far as it does not inhibit the reaction and dissolves a starting substance to an extent. For example, ethers such as tetrahydrofuran (THF), dioxane, ether, diethylene glycol dimethyl ether etc. are preferable. The reaction temperature is conventionally from xe2x88x9278 to 0xc2x0 C., and preferably from xe2x88x9278 to xe2x88x9240xc2x0 C.
The oxidation reaction of the aralkylthio group to an aralkylsulfonyl group can be carried out under the condition of oxidation which is conventionally used. For example, it can be carried out by interacting an inorganic peroxide such as hydrogen peroxide, or an organic peroxide such as m-chloroperbenzoic acid in a halogenated hydrocarbon solvent such as dichloromethane. It is preferable in the present reaction to coexist bases such as sodium bicarbonate, sodium carbonate and potassium carbonate.
The subsequent hydrolysis reaction can be carried out under the condition for hydrolysis which is conventionally used. For example, it can be carried out by interacting an appropriate acid such as hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid in an organic solvent or a mix solvent of water and an organic solvent.
The production process of the compound (I) according to the present invention has been described above, but the raw material compound in the production of the compound of the present invention may form a salt and a hydrate, and is not specifically limited unless the reaction is inhibited. Further, when the compound (I) according to the present invention is obtained as a free form, the above-mentioned compound (I) can be converted into a form of a salt. Further, various kinds of isomers provided for the compound (I) according to the present invention (for example, geometrical isomer, optical isomer based on asymmetric carbon, stereo isomer, tautomer etc.) can be purified and isolated by using conventional separating procedures (for example, recrystallization, diastereomeric salt method, enzyme fractionation method, various kinds of chromatography).
The compound represented by the above formula (I), a salt thereof or a hydrate of them can be formulated by a conventional method, and examples of a preferable preparation include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppository, injections, ointment, eye ointments, eye drops, nasal drops, eardrops, poultices, lotions etc. For preparations, fillers, binders, disintegrants, lubricants, colorants, and flavoring agents conventionally used, if necessary, stabilizers, emulsifiers, absorption accelerators, surfactants, pH regulators, antiseptics, antioxidants etc. can be used. Ingredients which are conventionally used for raw materials of pharmaceutical preparations can be formulated by a normal method. As these ingredients, for example, animal and vegetable oils such as soy bean oil, tallow and synthetic glyceride; hydrocarons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenic alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-hardened castor oil and polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxy ethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohol such as ethanol and isopropanol; polyvalent alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and dextrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate and aluminum silicate; purified water etc. may be proposed. Specifically, as fillers, for example, lactose, corn starch, white sugar, glucolse, mannitol, sorbit, crystalline cellulose, silicon dioxide etc.; as binders, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block copolymer, meglumine, calcium citrate, dextrin, pectin and the like; as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium etc.; as lublicants, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil etc.; as colorants, any colorant which is permitted to be added to pharmaceuticals; as flavoring agents, cocoa powder, menthol, aroma powder, peppermint oil, borneol, cinnamon powder etc.; and as antioxidants, which are permitted to be added to pharmaceuticals such as ascorbic acid and xcex1-tocopherol are used, respectively.
For example, (1) oral preparations are made as powders, fine granules, granules, tablets, coated tablets, capsules etc. according to a conventional method after adding fillers, and further, if necessary, binders, disintegrants, lubricants, colorants, flavoring agents etc. to the compound according to the present invention, a salt thereof or a hydrate of them. (2) In case of tablets and granules, sugar coating and gelatin coating, and additionally, if necessary, appropriate coating are allowed to be carried out. (3) In case of syrups, preparations for injection, eye drops and the like, pH regulators, resolving aids, isotonizing agents etc., and if necessary, solubilizer, stabilizers, buffers, suspensing agents, antioxidants etc. are added and formulated according to a conventional method. In case of the preparations, a freeze-dry product can be also made, and preparations for injection can be administered intravenously, subcutaneous, or in a muscle. Preferable examples of the suspensing agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, gum tragacanth powder, carboxymethyl cellulose sodium, polyoxyethylene sorbitan monolaurate etc.; preferable examples of the solubilizer include polyoxyethylene hardened castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate etc.; preferable examples of the stabilizer include sodium sulfite, meta sodium sulfite, ether etc.; preferable examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, chlorocresol etc. (4) Further, in case of external preparations, preparation process is not specifically limited, and the preparation can be produced by a conventional method. As the raw material of a base preparatiaon used, various raw materials which are conventionally used for pharmaceuticals, quasidrug, cosmetics etc. can be used. For example, raw materials such as animal and vegetable oils, a mineral oil, an ester oil, waxes, higher alcohols, fatty acids, a silicone oil, a surfactant, phosphatides, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, purified water etc. may be proposed. According to requirement, pH controller, an antioxidant, a chelating agent, antiseptic and fungicide, a coloring agent, flavors etc. can be added. Further, if necessary, ingredients having differential derivation action, blood flow accelerator, antibacterial, antiphlogistine, cell activator, vitamins, amino acids, a humectant, keratolysis medicine etc. can be formulated. The dose of the pharmaceuticals according to the present invention is different according to the extent of symptom, age, sexuality, body weight, administration form, modality of salt, the difference of sensitiveness for medicine, the specific modality of affection etc., but in case of an adult, approximately 30 xcexcg to 1000 mg per day for oral administration, preferably 100 xcexcg to 500 mg, and more preferably 100 xcexcg to 100 mg is in general administered at one time or several times. Approximately 1 to 3000 xcexcg/kg for injection administration, and preferably 3 to 1000 xcexcg/kg is in general administered at one time or several times.
The compound represented by the above formula (I) or a salt thereof or a hydrate of them has an excellent Na+ channel inhibitory action, and is useful as an Na+ channel inhibitor. Accordingly, the compound represented by the above formula (I), a salt thereof or a hydrate of them and the pharmaceutical composition containing thereof can exhibit an excellent treating or preventing effect on a disease against which the Na+ channel inhibitory action is useful for therapy and prevention, and are effective as an agent for treating or preventing, for example, arrhythmia (in addition, the removal of patient""s stress caused by an attack of atrial fibrillation, for example, palpitation, chest discomfort, heart failure, thrombus in left mitral, thromboembolism, seizure etc.), various nuralgias (for example, diabetic neuralgia, HIV neuralgia, postherpetic neuralgia, trigeminal neuralgia, stump pain, postspinal injury pain, thalamic pain, poststroke pain etc.) and an analgesic.